delta-allopregnenes and process



Patented Nov. 17, 1953 2,659,742 ALLALLOPREGNENES AND mocass George Rosenkranz, Stephen Kaufmann. and John Pataki, Mexico City, Mexico, assignors to Syntex S. A., Mexico City, Mexico, a corporation of Mexico No Drawing.

The present'invention relates to new cyclopentano-phenanthrene derivatives and process for producing the same. More particularly, the present invention relates to new allopregnane derivatives and to a novel process for preparing these derivatives. The new compounds, with which this present invention is particularly concerned. are derivatives of allopregnane having a hydroxy group at the 17d position and a hydroxy or acyloxy group in the 21-position. Compounds of this character are especially su table as therapeutics and/or intermediates for the production of therapeutically useful products.

The starting material for the production of the aforesaid derivati es is the allopregnane- 35.1%.21-trlol-20-one (Reichsteins substance P) esterified by a low fatty acid in the ill-position, as for example, acetic acid, propionic acid, etc. It has been found, in accordance with the present invention, that when the aforesaid compound is treated with a mol quantity of bromoacetamide in the presence of a weak organic base, such as pyridine, an oxidation of the hydroxyl group in position 3 takes place with the production of allopregnane 17,21 diol 3,20 dione 21-acylate.

It has been further found that upon treatment of allopregnane 17a,21-diol-3,20-dione zl-acylate with 1 mol of bromine a new compound 2-bromoallopregnane-17a,21-diol-3,20-dione 21-acylate is produced. Thereafter, upon. dehydrobromination the unsaturated or A corresponding derivative is produced, 1. e. A -a110p1'BgIlene-17a,

Application January 23, 1950, Serial No. 140,153

5 Claims. (01. 260-3974) 2 in the firstrstep of the present reaction may be exemplified by the following formula:

wherein R is an aromatic or aliphatic radical and X is selected from the group consistingof bromine or chlorine. In place of pyridine, which is preferred for the present reaction, other weak organic bases may be used, as for example, collidine, lutidine or diethyl aniline. For the dehydrobromination step of the present process the use of'collidine is preferred. However, in

to stand for a prolonged period of the order of one day at room temperature and thereafter concentrated in vacuo. The concentrate may then be diluted with water and the precipitate filtered and washed with water. Thereafter the precipitated diketone may be recrystallized from ethanol. For the bromination step the diketone is preferably dissolved in glacial acetic acid and treated with amolar quantity of bromine for each mol of diketone-in the presence of a few drops of concentrated hydrobromic acid. In the.

alternative the diketone may be treated with chlorine to produce the corresponding chloro compound. The reaction mixture produced after a short period of time, as for example ten minutes, is then poured into water and the precipitate filtered and washed with water. The bromo-ketone thus produced may be also recrystallized as from ethanol. The dehydrobromination of the bromo-ketone compound, as previously set forth is preferably performed by the There may also be produced Q-balo-allouse of collidi'ne. Preferably the conmound is pregnane 17a,21 diol 3,20 dione 21 10y}- refluxed with the collidine for a period of time ates which may be indicated by th following of the order of 45 minutes. The reaction mixformula: ture is then cooled, treated with ethyl acetate 5 and washed with a dilute mineral acid, as for (T example sulfuric acid, and then with water to I neutrality. The solution is then dried and con- CH: centrated until crystallization begins. It is then I cooled and the compound is then filtered and recrystallized from ethyl acetate.

The corresponding A -allopregnene-lhz1- diol-3,20-dione can be produced by mild hydrol- X ysis or saponification of the corresponding 21- 0 acylate. 15

The foregoing reactions may be exemplified H by the following equation: wherein X is selected from the group consisting CH3 CH3 CIIlhOAcyl C HaOAcyl on, C0 en 1 mo] Bromine CH: CH:

('JllzOAcyl il'hOAcyl c o 0 0 :--on li o):

l Dchydrobrominniion Br oi 0 wild iilponiflcation GUIDE 0 0 CH3(\ u- 0 H o In the foregoing formula the acyl group indiof bromine or chlorine and R is the residue of a cated is the residue of a lower fatty acid. There lower fatty acid.

may therefore be produced. in accordance with There may also be produced A -allopregnenethe foregoing, al1opregnane-17a,21-diol-3,20- W 17a.21-diol-3,20-dione 21-acylates which may be dione 21-acylates which may be indicated by the dica d by e following fo following formula: 0 Ii;

C H: C H2 0 R c n o R l 5 C H: A: o

crib 3 I Q 17 Q wherein R is the residue of a lower fatty acid. wherein R is the residue of a lower fatty acid. 75 The following specific examples serve to illustrate the present invention but are not intended to limit the same: Example I Example I! To a solution of grams of allopregnane 17a,21-diol-3,20-dione zl-monoacetate in 3 liters of glacial acetic acid, 3 drops of hydrobromic acid and 4.1 grams of bromine dissolved in148 cc. of

glacial acetic acid were added. After standing for 10 minutes the solution was poured into water and the precipitate filtered oil and washed with water. The dried product was recrystallized from methyl alcohol. The 2-bromo-allopregnane- 17a,21-diol-3,20-di0ne 21-monoacetate melted at 200201 C. with a decomposition.

Example III 6 grams of 2-bromo-allopregnane-17a,2l-diol- 3.20-dione zl-monoacetate were refluxed in 24 cc. of collidine for 65 minutes. The solution was cooled to room temperature and poured into diluted sulfuric acid. The precipitated product was filtered off, Washed thoroughly with water and dried. After several recrystallizations from ethyl acetate the A -allopregnene-17,21-diol-3,20- dione 21-monoacetate melted at 260-263 C.

Example IV 190 mg. of A -allopregnene-17a,21-diol-3,20-

dione 21-monoacetate were refluxed with 300 mg.

of potassium bicarbonate in 55 ml. of 9.0 per cent methanol for one and a half hours. After adding 10 ml. of water the solution was concentrated in vacuo and extracted with ethyl acetate. The ethyl acetate solution was dried with anhydrous sodium sulfate, filtered and evaporated to a small volume. The crystals of the A -allopregnene- 17. 21-diol-3.20-dione, after several recrystallizations from ethvl acetate, melted at 235-239 C.

I It will be obvious to those skilled in the art that various changes may be made without departing from the spirit of the invention and therefore the invention is not limited to what is described in the specification but only as indicated in the appended claims.

We claim:

1. A A allopregnene 17c.21 diol 3.20- dione 21-acylate having the following formula:

CH2OR wherein R is a lower fatty acid radical.

2. A A allopregnene 1%,21 diol 3,20- dione 21-acetate having a melting point of 260- 263 C.

3. A A allopregnene 17a,2f diol W0- dlone having a meltingpoint of 235-239 C.

4. A process for the production of Ai -allopregnene-17a.2l-diol-3,20-dione 2l-acylate comprising treating allopregnane-3p,17.a,21-trio1-20- one 21-acylate with a compound selected from the group consisting of compounds having the formula:

wherein R is selected from the group consisting of aromatic and aliphatic radicals, R is an allphatic radical and X is selected from the group consisting of bromine and chlorine in the presence of a weak organic base to produce allopregnane-17a,21-diol-3,20-dione 2l-acylate, brominating, allopregnane-17a,21-diol-3,20 dione 21- acylate' to produce 2-bromo-allopregnane-17,21- diol-3,20-dione 21-acy1ate and subjecting 2- bromo-allopregnane-17e,21-diol-3,20-dione 21- acylate to dehydrobromination.

.5. A process for the production of A -allopregnene-17a,21-diol-3,20-dione 2l-acylate comprising treating sl1opregnane-3p,17,21-triol-20- one 21-acy1ate with 1 mol of bromoacetamide in the presence of pyridine to produce allopregnane- 17a,21.-diol-3 20-dione 21-acylate, brominating allopregnane-17a,2l-diol-3,20-dione 21-acylate to produce z-bromo-allopregnane-17a,21ediol-3,20- dione 21-acylate and treating 2-bromo-allopregnrne-17,21-diol-3,20-dione 21-acylate with collidine.

6. A process for the production of A -allopregnene-1'1a,21-diol-3,20-dione comprising treating allopregnane-3;3,l7a,21-triol-20-one 21-acylate with a compound selected from the group consisting of compounds having the formula:

of aromatic and aliphatic radicals, R is an aliphatic radical and X is selected from the group consisting of bromine and chlorine, in the presence of a weak organic base, to produce allopregnane-17a,2l-diol-3,20-dione 21-acylate, brominating al1opregnane-17a,21-diol-3,20-dione 21-acylate to produce 2-bromo-allopregnane-17,21-di0l- 3,20-dione 2l-acylate, subjecting 2-bromo-allopregnane-17a,21-diol-3,20-dione 21-acylate to dehydrobromination to produce A fi-allopregnen'e- 7 8 17.1.21-dio1-3 ZO-dione zl-acylate and subjecting Number Name Date the A 'mflnprcgncne-17a,21-dio1-3,20-di0ne 21- 2,401,775 Reichsteln June 11, 1946 acylnte to mild hydrolysis. 2,441,560 Butenandt May 18. 1948 GEORGE ROSENKRANZ.

STEPHEN KAUFMANN. 5 FOREIGHPATENTS JOHN PATAKL Number Country Date 235,192 Switzerland Mar. 16, 1945 References cube in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Fieser et a1., Natural Products Related to Phe- Nnmber Name Date 10 nanthrene, 3rd ed., p. 262 1949) 2,143,453 Ruzicka Jan. 10, 1939 I 2,260,328 Miescher Oct. 28, 1941 

1. A $1,2-ALLOPREGNENE-17A,21 - DIOL - 3,20DIONE 21-ACYLATE HAVING THE FOLLOWING FORMULA: 